This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cells in the nervous system use intercellular signaling cues extensively to properly the extend neurites, navigate to and recognize target cells and form and maintain synaptic contacts. The ability to predict secreted proteins from whole genomes has led to the conclusion that perhaps as much as one third of all proteins encoded are secreted into the extracellular space. Given the complexity of nervous systems it stands to reason that many of these secreted proteins act in the patterning of the nervous system. We have generated a library of predicted secreted proteins from the C. elegans genome. We will take a systematic approach using RNA interference (RNAi) to knockdown of all 7,460 predicted secreted proteins and evaluate the effect of this RNAi on multiple aspects of neural development. A preliminary characterization will be done to identify molecules that have an effect on neuronal patterning, and a secondary level quantitative analysis will be done on those molecules. We are using a synthetic lethal screening approach to characterize these molecules first, and then we will examine the outgrowth and synaptic morphology in mutants for genes that demonstrate an effect. Understanding how the nervous system is patterned has long been a goal of neurobiology. A multitude of studies have demonstrated the importance of extracellular proteins on all aspects of neuronal development. The ability to systematically evaluate the effect of loss of function of all secreted proteins has only recently become available. This will provide many novel insights into an extremely complicated part of development.